Cellular and physiological studies of mouse models of diabetes and exocrine deficiency due to mutations in carboxyl-ester lipase

We have recently discovered a novel monogenic diabetes syndrome with combined endocrine and exocrine pancreatic dysfunction, which is caused by mutations in the carboxyl-ester lipase gene (Ræder et al, Nature Genetics, in review). Our findings link diabet es to dysfunction of a lipase in the pancreatic acinar cells. This finding point to a new mechanism for the development of diabetes, and extend the number of potential associations between endocrine and exocrine pancreatic dysfunction. Recent reports indi cate a higher prevalence than previously supposed of exocrine pancreas dysfunction in patients with type 1 and 2 diabetes and MODY 5. The molecular factors contributing to this exocrine insufficiency remain elusive. The reason why mutations in carboxylest er lipase should cause diabetes and exocrine dysfunction is so far unknown. The aim of the current project is to elucidate the disease mechanism. To this end, we plan to investigate various cell lines stably transfected with wild-type and mutant carboxyl- ester lipase gene, and to phenotype newly constructed mouse models carrying null or conditional mutations in the carboxyl-ester lipase gene. The cell lines and mouse models will be important tools for a number of investigations. In order to initiate these analyses, Dr. Njølstad was a visiting professor in Director Kahn?s Laboratory, Joslin Diabetes Center, Harvard Medical School, from August 2004 to July 2005. PhD students Helge Ræder (MD) is currently continuing his work in Dr Kahn's laboratory. The proj ect aims at gaining new insight into the etiology and pathogenesis of diabetes and may have implications for diagnosis and treatment of patients with a disease that is reaching epidemic proportions world-wide.